Slowly Progressive Limb-Girdle Weakness and HyperCKemia – Limb Girdle Muscular Dystrophy or Anti-3-Hydroxy-3-Methylglutaryl-CoA-Reductase-Myopathy?

Abstract

Background: Anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)-myopathy is a usually rapidly progressive form of immune-mediated necrotizing myopathy (IMNM). Rarer clinical courses show slow progression and resemble the phenotype of limb-girdle dystrophy (LGMD). Objective: We demonstrate the difficulties in differentiating LGMD versus anti-HMGCR-myopathy. Methods: We report on a 48-year-old patient with slowly progressive tetraparesis and hyperCKemia for more than 20 years. Results: Due to myopathic changes in initial and second muscle biopsy and typical clinical presentation, the patient was diagnosed with LGMD 20 years ago; despite comprehensive genetic testing including exome diagnostics, the genetic cause of disease could not be identified. Finally, HMG-CoA reductase antibodies were detected, confirming the diagnosis of anti-HMGCR-myopathy. By re-work-up of a second muscle biopsy specimen from year 2009, the diagnosis of a IMNM was made in retrospect. Seven cycles of high-dose immunoglobulins were administered; patient reported outcome measures have mildly improved. Conclusion: Patients with clinical LGMD phenotype, degenerative changes in muscle biopsy but without genetic confirmation of the disease should be tested for HMG-CoA-myopathy, thereby allowing for an early start of treatment.

Absence of Pathogenic Mutations and Strong Association With HLA-DRB1*11:01 in Statin-Naïve Early-Onset Anti-HMGCR Necrotizing Myopathy

“…A recent retrospective study in patients with IMNM showed that muscle MRI can be useful for monitoring disease activity and that the percentage of STIR+ muscles correlated with higher risk of fat replacement at follow-up, but a specific pattern of involvement was not identified either. 49 Regarding young statin-naïve patients, only few imaging data from case reports are available with similar findings, 11,17 and there are not larger series to allow a proper comparation.…”

“…13,16,19,20 Two recent case reports have attested to muscle imaging evidence of progression from muscle edema to fatty infiltration over the years, demonstrating irreversible muscle damage. 11,17 This fact would suggest that treatment must be prompt, given that immunomodulatory therapy initiated years after onset is usually unsuccessful in controlling the disease.…”

“…5,10 A distinct anti-HMGCR IMNM phenotype has been reported in very young statin-naïve patients, with subacute clinical presentation and chronic progression mimicking muscular dystrophy. Cases of young asymptomatic patients with anti-HMGCR antibodies and high CK levels, although extremely rare, have been reported, with either progression of weakness without treatment 11 or complete resolution of CK elevation after treatment with methotrexate and IVIG. 12 Some children and young adults with anti-HMGCR IMNM respond reasonably or very well to immunotherapy.…”

Rare disease informs mechanism and possible treatment of statin-associated myopathy

“…In others, anti-HMGCR autoantibodies develop without an apparent trigger. The muscle disease can manifest as a rapidly progressive form of IMNM, but in rarer cases shows slow progression and can be erroneously diagnosed as limb-girdle muscular dystrophy (LGMD) ( 9 , 10 ).…”